A phase 3 randomized clinical trial using a once‐weekly glucagon‐like peptide‐1 receptor agonist in adolescents and young adults with hypothalamic obesity

AIM: To evaluate the efficacy, safety and tolerability of a glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) in patients with hypothalamic obesity (HO). MATERIALS AND METHODS: A two‐arm, randomized, multicentre, double‐blind, placebo‐controlled trial was conducted in 10‐ to 25‐year‐olds with hypothalamic injury following intracranial tumour and HO. Participants were randomized to once‐weekly subcutaneous injections of a GLP‐1 RA exenatide 2 mg (ExQW) or placebo for 36 weeks. The primary efficacy endpoint was 36‐week % change in body mass index (BMI). Secondary outcomes included change in body composition (by dual energy x‐ray absorptiometry). RESULTS: Forty‐two participants were randomized to ExQW (n = 23) or placebo (n = 19). Participants were 5 ± 2 years (mean ± SD) postdiagnosis and development of HO (BMI 37.3 ± 7.1 kg/m(2)). In intention‐to‐treat analysis, the effect of 36‐week ExQW vs. placebo on % Δ BMI was not significant (estimated treatment difference −1.7 ± 1.8%, 95% CI −4.1 to 0.6%, P = .40); however, total body fat mass was reduced (estimated treatment difference −3.1 ± 1.4 kg, 95% CI −5.7 to −0.4 kg, P = .02). There was a significant reduction in waist circumference (estimated effect of treatment −3.5 [95% CI −5.5 to −1.6] cm, P = .004). All patients treated with placebo increased % of adipose tissue, while 50% treated with ExQW had reductions (P < .001). Mean HbA1c, glucose tolerance and serum lipids did not change significantly with therapy. ExQW was well tolerated. The most frequent adverse events were transient gastrointestinal disturbances (ExQW vs. placebo: nausea 6/23 vs. 3/18, vomiting 4/23 vs. 4/18 and diarrhoea 7/23 vs. 3/18). CONCLUSIONS: GLP‐1 RAs are a promising and safe treatment to improve or stabilize HO in children and young adults.